Replication-competent murine retroviruses induce various types of hematopoietic tumors upon inoculation into mice. Recombination studies using molecularly cloned, viral genomes show that the long terminal repeat (LTR) is the primary genetic determinant of the viral disease inducing phenotype. Transcriptional tissue specificity of several viral LTRs shows an excellent correlation with the type of tumor induced by each virus. The central focus of the work described in this proposal is an assessment of the role of tissue specific differences in transcriptional activity in leukemogenicity. The nature of the molecular events involved in tissue specificity will be studied in detail primarily using the thymomagenic virus, SL3-3, and the non-leukemogenic virus, Akv. These studies will focus on identification of sequences at the single nucleotide level that are responsible for differences in tissue specificity and on identification of proteins that interact differentially with enhancer elements in the LTR. These studies are expected to lead to insight into the normal regulation of cell-type specific gene expression. The means which tissue specific regulation of gene expression alters viral leukemogenicity will also be studied in detail. From the standpoint of viral genetics, these studies are aimed at identifying the minimal changes necessary to convert a non- leukemogenic virus into one that induces thymic lymphomas. Two mechanisms by which altered tissue specificity could determine leukemogenicity will be investigated. One is whether transcriptional elements alter viral tissue tropism, while the other is whether these elements alter oncogene expression in a manner that alters tumorigenicity.